Amantadine-Induced Livedo Racemosa

Case Report

Patient 1

The patient is a 57-year-old Caucasian woman with Parkinson’s disease that started at age 50 with a resting tremor of legs. She received amantadine 200 mg daily with good response. She was referred to the Dermatology Department due to asymptomatic rash on her knees within the first year after receiving amantadine.

On physical exam, she had erythematous to violaceus net-like mottled patches on knees with irregular and broken segments, demonstrating a pattern of livedo racemosa (Figure 1A). She also had bilateral swelling of lower extremities and associated burning sensation. A cutaneous biopsy from the pallor area of the livedo racemosa demonstrated normal epidermis and partial thrombotic occlusion of blood vessels (arterioles) by blood red cells and fibrin in deep dermis and subcutis (Figure 1B and C). The histopathological diagnosis of thrombotic vasculopathy was established. The neurology consult and a peripheral nerve biopsy showed enlargement of epineurum and perineurum by collagen fibers and the blood vessels (vasa nervorum) associated with hyaline deposition in the vessel walls. The number of myelinated fibers and axonal degeneration are reduced with lack of inflammatory infiltrate or vascular thrombosis. An extensive workup was performed to rule out differential diagnoses of livedo racemosa–related conditions, and a diagnosis of amantadine-induced livedo racemosa was made. The only positive exam was rheumatoid factor 53.5 IU/mL (normal range < 20 IU/mL by nephelometric method). She denied using any other drugs, and she did not have any other joint symptoms. On follow-up 2 months after discontinuation of amantadine, the livedo racemosa faded. Three years later the patient noticed recurrent episodes of arthralgias and symmetrical joint swelling on her hands, and a diagnosis of rheumatoid arthritis was made and methotrexate 20 mg/week was started and she had a good outcome.

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Figure 1.

Case 1. (A) Livedo racemosa characterized by mottled erythematous to violaceus net-like patches on knees, showing irregular and broken segments (demarked pallor area where biopsy was performed). (B) Thrombi present inside a blood vessel in dermoepidermal junction (hematoxylin–eosin, 200×). (C) Detail of thrombotic vasculopathy (hematoxylin–eosin, 400×).

Patient 2

A 54-year-old Caucasian man with a previous history of Parkinson’s disease, on amantadine 300 mg daily, was referred by his neurologist to the Dermatology Department due to mottled discoloration of his legs typical of livedo racemosa (Figure 2A and B). He also had bilateral swelling of the lower extremities. The patient noticed that his symptoms were present within the first 6 months of commencing amantadine. All blood tests were normal or negative. The level of lipoprotein(a) was elevated (89 mg/dL; normal range < 9 mg/dL, immunoturbidimetric method).

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Figure 2.

Case 2. (A) Livedo racemosa characterized by mottled network erythematous to violaceus macules on thighs, knees, and legs showing irregular and broken segments. (B) Demarked pallor area where cutaneous biopsy was performed. (C) Thrombi present inside a blood vessel in upper dermis (hematoxylin–eosin, 100×). (D) Detail of thrombotic vasculopathy (hematoxylin–eosin, 400×).

Histopathology of pallor area of the livedo racemosa demonstrated hyaline microthrombi in blood vessel of superficial dermis (Figure 2C and D). A diagnosis of amantadine-induced livedo racemosa was established.

Discussion

Amantadine is a synthetic antiviral agent initially launched in the market to prevent and treat infection by influenza A virus. ³ Nowadays this drug is used to treat Parkinson’s disease, drug-induced extrapyramidal symptoms, fatigue related to multiple sclerosis, and chronic hepatitis C resistant to standard treatments. ³ Side effects commonly reported with amantadine are nausea, insomnia, livedo reticularis, dizziness, and lower extremity edema, possibly due to increased vascular permeability. ³ Our 2 patients presented lower extremity edema. Some authors proposed that leg edema can be seen as an isolated finding, ⁵ and others claim that it may occur only when livedo reticularis is present. In our patients, the lower extremities’ swelling and livedo racemosa started at the same time as were reported by the both patients.

Our patients are different from the previous reported cases in the literature by the presence of livedo racemosa, in contrast to livedo reticularis, and the cutaneous lesions localized only in the knees in Patient 1, and on the legs in Patient 2. Another interesting finding was the histopathological exam, which in both cases showed a thrombotic vasculopathy. Livedo racemosa differs from livedo reticularis by irregular broken circular morphology and more widespread, generalized distribution, and the histology is similar and demonstrates a thrombotic vasculopathy.^6,7

Lipoprotein(a) is a unique lipoprotein consisting of a low-density lipoprotein-like moiety covalently linked to apolipoprotein(a), a homolog of the fibrinolytic proenzyme plasminogen. Several mechanisms accounting for the ability of apolipoprotein(a) to inhibit fibrinolysis have now been proposed, including inhibition of plasminogen and tPA binding to fibrin and inhibition of tPA-mediated Glu-plasminogen to Lys-plasminogen by plasmin, which greatly influences plasminogen activation efficiency on fibrinolysis. ⁸ Maybe in our Patient 2 the excessively elevated levels of lipoprotein(a) could be part of the thrombotic process of the cutaneous blood vessels in a clinical scenario of amantadine-induced functional vascular alterations. Amantadine is known to cause depletions of catecholamines at the peripheral nerve terminals, and this is probably the mechanism of the vascular effect, causing venodilation leading to development of livedo reticular.^9,10

Vollum et al ¹¹ studied 21 women and 15 men with livedo reticularis due to amantadine treatment and performed skin biopsies in 6 of these patients. Five patients had normal skin biopsies and one a small venule partially occluded by organizing thrombus, but without signs of vasculitis, similar to findings observed in our patients. Vollum et al ¹¹ suggested that in cases of amantadine-induced livedo reticularis this vascular pattern is consistent with a physiological rather than pathological etiology of livedo. However, our cases showed partial thrombotic occlusion of blood vessels and a pattern of livedo racemosa. The histopathological findings of thrombotic vasculopathy must alert the clinicians to investigate other associated comorbidities related to vessel occlusions in this clinical setting: in case 1 the patient displayed an elevated rheumatoid factor, and in case 2 there was association with elevated levels of lipoprotein(a). Patient 1 developed paresthesis and signs of peripheral neuropathy in a pattern similar to that previously reported by Shulman et al. ⁴ She eventually developed rheumatoid arthritis after 2 years. Several studies have suggested that rheumatoid arthritis confers a prothrombotic state featured by abnormalities in coagulation and fibrinolytic systems together with an altered state of platelet reactivity. ¹⁰ It is conceivable that these findings may be partly instrumental for the observed increased risk for adverse cardiovascular events in rheumatoid arthritis. ¹²

Finally, the cases reported herein reinforce that amantadine causes chronic livedo and may induce neuropathy. Prior to commencing amantadine, thorough history, phy-sical exam, and in certain cases further investigation of systemic conditions, particularly thrombophilic disorders, are helpful to prevent adverse reactions.